The prevalence of obesity in the U.S. population (26% of people in all age groups) and its increased risk for life-threatening or chronic diseases, such as cancer, hypertension and heart disease, have caused the NIH in 1985 to declare obesity a disease. Reduction of excess weight is associated with lowered health risk. Unfortunately, predictable pharmacologic means for long term weight reduction are still lacking despite a large number of available drugs. Such drugs, primarily of the amphetamine class, have been shown to provide only modest weight reduction over the short term. In addition, their effectiveness is mitigated by rebound eating, and by abuse and addiction.. The neuropharmacology of appetite and satiety are just beginning to be understood at the molecular level, and the number of potential pharmacologic means to alter feeding behavior has increased accordingly. Enhancement of appetite by newly discovered neuropeptides, for example, must await the discovery of bioavailable nonpeptide agents. Of several central mechanisms for controlling appetite and feeding, there is considerable evidence that the opiod system plays a major role. The expanding body of pharmacological data pertaining to opiates suggests a clear novel approach to a safe appetite suppressant. Several existing opiate antagonists inhibit feeding, although the available ones produce any combination of short action, tolerance, or dysphoria. However, since individual antagonists have one or another useful property, the design of opiate antagonists with superior characteristics should be possible. Informed by strategies from opiate receptor pharmacology, Nova is in the process of synthesizing a series of novel opiate antagonists led by a proprietary compount designated NPC-168. Phase I support is requested to establish and carry out molecular pharmacology and feeding trials of several such compounds which will be available for evaluation for the Phase I grant period. Successful compounds which pass this screen will then be more vigorously evaluated (Phase II) for such parameters as tolerance, metabolic alterations and acute and chronic toxicity.